Parasitic nematodes infect more than two billion people, causing significant morbidity and mortality. Characterization of the genomes of parasitic nematode provides fundamental molecular information that can be used to accelerate basic research and the development of new diagnostics and therapeutics, which are a public health priority due to the limited number of currently available drugs, the limited efficacy against some species (e.g., whipworm) and increasing anti-drug resistance. To that end, we have established an extensive genomic database by sequencing and annotating genomes and transcriptomes of nematode parasites of medical importance, including representative human parasites that span the major taxonomic clades in the phylum Nematoda. Furthermore, we focused analysis on biochemical pathways conserved and/or taxonomically restricted and condition-specific, identifying proteins that may prove useful as drug targets. The three aims of this proposal build on our progress by taking advantage of the generated multi-dimensional resource to undertake a systems biology approach aimed at promoting discovery and development of new therapeutics. First, we will reconstruct metabolic networks of both intestinal and filarial parasits, and analysis will focus on pan-conserved chokepoint enzymes in taxonomically restricted and differentially expressed metabolic pathways as potential targets for anthelmintic drugs. Second, we will perform drug-sensitivity assays to test our hypothesis and validate the predicted broad control potential of the pan-phylum targets. Third, we will perform lead optimization and demonstrate increased potency and selectivity of nematode metabolic enzyme inhibitors, followed by validation of target inhibition in vitro and in vivo. Keys to our overall approach include the selection of species of parasites that span the evolutionary extremes of the Phylum (supporting the creation of a pan-phylum metabolic pathway database with the broadest scope and optimal predictive value), the development of a prioritization protocol that leverages systems biology and cheminformatics for target and drug prioritization, followed by experimental validation and, in turn, identification and optimization of leads. The expected outcome will facilitate and promote the discovery and development of novel interventions to treat and control these important parasites and reduce their associated morbidity and mortality.